The Cyclin dependent kinase family (Cdks) have long been considered as the master regulators of the cell cycle, but more and more diverse protein kinases are emerging which play important role in cell cycle progression. One of these is the polo-like kinase family (Plks).
Plks are serine/threonine kinases that play important role in regulating cell circle. There are four Plks disclosed in the state of the art, i.e. Plk1, Plk2, Plk3 and Plk4. Plks play important role in the regulation of the eukaryotic cell cycle (e.g. regulation of the mitosis in mammalian cells). Especially, Plk1 play a central role in the regulation of mitosis (Glover et al. 1998, Genes Dev. 12: 3777-87; Qian et al. 2001, Mol Biol Cell. 12: 1791-9). Overexpression of Plk1 seems to be strongly associated with neoplastic cells including cancers (WO2004014899). Overexpression of Plk1 has been proven to be associated with various types tumor such as non-small cell lung cancer, aquamous cell carcinomas, breast, ovary or papillary carcinomas as well was colorectal cancers (Wolf et al. 1997, Oncogene 14: 543-549; Knecht et al. 1999, Cancer Res. 59: 2794-2797; Wolf et al. 2000, Pathol Res Pract. 196: 753-759; Weichert et al. 2004, Br. J. Cancer 90: 815-821; Ito et al. 2004, Br. J. Cancer 90: 414-418; Takahashi et al. 2003, Cancer Sci. 94: 148-152).
It is reported that Plk1 is conserved from yeast to man and has been involved in numerous mitotic process including activation of Cdc25C and Cdk1/Cyclin B at the G2-M transition, centrosome maturation, spindle formation and assembly. In the later stages of mitosis, Plk1 is also involved in separation of sister chromatids, activation of components of the anaphase-promoting complex and septin regulation during cytokinesis.
Lots of pteridinone derivatives as Plk inhibitors were disclosed in the prior art with antiproliferative activity. For example, WO2003020722 and WO2004076454 describes pteridinone derivatives, preparation process and pharmaceutical compositions which were used for the treatment of diseases related to the activity of cyclin kinase, and characterised by overexpression or abnormal cell proliferation. WO01/019825 describes the use of pteridinone derivatives for the treatment of neoplastic and viral diseases. Because of the drug resistance of different type tumor, new drugs are urgently needed to treat tumor. The other patent applications such as WO2004076454, WO2006018220, US20040176380, WO2007135374, WO2006018185, WO2006058876, WO2006018222 and WO2006018182 also disclose the compounds as Plk inhibitors.
However, although several Plk kinase inhibitors were disclosed, safe Plk inhibitors with improved pharmacokinetics are also needed.
The purpose of the present invention is to provide a Plk kinase inhibitor of novel structure with more effective activities, safety and less toxity, which is used to treat cell proliferation disorder such as cancer, infections, inflammatory and autoimmune disease.